5-Beta, 14-Beta-Androstane Derivatives Useful For The Treatment Of Proteinuria, Glomerulosclerosis And Renal Failure

Abstract

Compound of formula (I), wherein the symbol have the meaning reported in the text; for preparing a medicament for the prevention and/or treatment of proteinuria, glomerulosclerosis or renal failure.

1 . Compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein: 
         the symbol   represents a single or a double bond; 
         Y is oxygen or guanidinoimino when   in position 3 is a double bond; 
         Y is hydroxy, OR 4  or SR 4 , when  in position 3 is a single bond and can have an alpha or beta configuration; 
         R is an unsubstituted or substituted 3-furyl or 4-pyridazinyl group; 
         R 1  is hydrogen; methyl; ethyl or n-propyl substituted by OH or NR 5 R 6 ; 
         R 2  is hydrogen or together to R 3  is a bond of an oxirane ring; 
         R 3  is hydrogen or together to R 2  is a bond of an oxirane ring; 
         R 4  is hydrogen; methyl; C2-C6 alkyl or C3-C6 alkenyl or C2-C6 acyl, these alkyl, alkenyl and acyl groups being unsubstituted or substituted by a quaternary ammonium group or one or more OR 7 , NR 8 R 9 , formyl, amidino, guanidinoimino or by NR 8 R 9  and hydroxy; 
         R 5 , R 6  are independently hydrogen; methyl; C2-C6 alkyl unsubstituted or substituted by one NR 10 R 11 , or NR 10 R 11  and hydroxy, or R 5  and R 6  taken together with the nitrogen atom form an unsubstituted or substituted saturated or unsaturated penta- or hexa-monoheterocyclic ring, optionally containing another heteroatom chosen from oxygen or sulfur or nitrogen; 
         R 7  is hydrogen, methyl or C2-C4 alkyl, this alkyl being unsubstituted or substituted by one or more NR 10 R 11  or by NR 10 R 11  and hydroxy; 
         R 8 , R 9  are independently hydrogen; methyl; C2-C6 alkyl or C3-C6 alkenyl, these alkyl and alkenyl groups being unsubstituted or substituted by one or more NR 10 R 11 , or NR 10 R 11  and hydroxy, or R 8  and R 9  taken together with the nitrogen atom form an unsubstituted or substituted saturated or unsaturated penta- or hexa-monoheterocyclic ring, optionally containing another heteroatom chosen from oxygen or sulfur or nitrogen, or R 8  is hydrogen and R9 is amidino; or NR 8 R 9  represents propargylamino, 
         R 10 , R 11  are independently hydrogen, C1-C6 alkyl, or R 10  and R 11 , taken together with the nitrogen atom form a saturated or unsaturated penta- or hexa-monoheterocyclic ring; for use as antiproteuremic agent. 
       
     
     
         2 . Compound of formula (I) of  claim 1 , for use as anti-glomerosclerotic agent. 
     
     
         3 . Compound of formula (I) of  claim 1 , for use as anti renal failure agent. 
     
     
         4 . Compound of formula (I) of  claim 1 , selected from the group consisting of:
 17-β-(3-furyl)-5-β-androstane-3-β, 14-β, 17-α-triol;   3-β-(2-hydroxyethoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-aminoethoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(3-aminopropoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-methylaminoethoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-(1-pyrrolidinyl)ethoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-(3-(1-pyrrolidinyl)propoxy)ethoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(3-(1-pyrrolidinyl)propoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-(1-imidazolyl)ethoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-(2-imidazolin-2-yl)ethoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-(2-amidino)ethoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-(2-(1-pyrrolidinyl)ethoxy)ethoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-guanidinoethoxy)-17-β-(3-furyl)5-β-androstane-14-β, 17-α-diol;   3-β-(3-guanidinopropoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(3-amino-2-hydroxypropoxy)-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2,3-diaminopropoxy)-17-β-(3-furyl)5-β-androstane-14-β, 17-α-diol;   17-β-(3-furyl)-17-α-methoxy-5-β-androstane-3-β, 14-β-diol;   17-β-(3-furyl)-17-α-(2-(1-pyrrolidinyl)ethoxy)-5-β-androstane-3-β, 14-β-diol;   17-β-(3-furyl)-17-α-(3-aminopropoxy)-5-β-androstane-3-β, 14-β-diol;   3-β-(2-(1-pyrrolidinyl)ethoxy)-17-β-(3-furyl)-17-α-methoxy-5-β-androstan-14-β-ol;   3-β, 17-α-bis(2-(1-pyrrolidinyl)ethoxy)-17-β-(3-furyl)-5-β-androstan-14-β-ol;   3-β, 17-α-bis(3-aminopropoxy)-17-β-(3-furyl)-5-β-androstan-14-β-ol;   14-β, 17-α-dihydroxy-17-β-(3-furyl)-5-β-androstan-3-one,   3-guanidinoimino-17-β-(3-furyl)-5-β-androstane-14-β, 17-α-diol;   17-β-(4-pyridazinyl)-5-β-androstane-3-β, 14-β, 17-α-triol;   3-β-(2-hydroxyethoxy)-17-β-(4-pyridazinyl)5-β-androstane-14-β, 17-α-diol;   3-β-(3-aminopropoxy)-17-β-(4-pyridazinyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(2-(1-pyrrolidinyl)ethoxy)-17-β-(4-pyridazinyl)-5-β-androstane-14-β, 17-α-diol;   3-β-(3-(1-pyrrolidinyl)propoxy)-17-β-(4-pyridazinyl)-5-β-androstane-14-β, 17-α-diol;   17-β-(4-pyridazinyl)-17-α-(3-aminopropoxy)-5-β-androstane-3-β, 14-β-diol;   3-β-(2-(1-pyrrolidinyl)ethoxy)-17-β-(4-pyridazinyl)-17-α-methoxy-5-β-androstan-14-β-ol;   3-β-(2-(1-pyrrolidinyl)ethoxy)-17-β-(4-pyridazinyl)-17-α-(3-amino-propoxy)-5-β-androstan-14-β-ol;   14-β,17-α-dihydroxy-17-β-(4-pyridazinyl)-5-β-androstan-3-one;   3-guanidinoimino-17-β-(4-pyridazinyl)-5-β-androstane-14-β, 17-α-diol;   14-β, 15-β-epoxy-17-β-(3-furyl)-5-β-androstane-3-β, 17-α-diol;   3-β-(2-hydroxyethoxy)-14-β, 15-β-epoxy-17-β-(3-furyl)-5-β-androstan-17-α-ol;   3-β-(3-aminopropoxy)-14-β, 15-β-epoxy-17-β-(3-furyl)-5-β-androstan-17-α-ol;   3-β-(2-(1-pyrrolidinyl)ethoxy)-14-β, 15-β-epoxy-17-β-(3-furyl)-5-β-androstan-17-α-ol;   3-β-(3-(1-pyrrolidinyl)propoxy)-14-β, 15-β-epoxy-17-β-(3-furyl)-5-β-androstan-17-α-ol;   3-β-(2-(1-pyrrolidinyl)ethoxy)-17-β-(3-furyl)-17-α-methoxy-14-β, 15-β-epoxy-5-β-androstane;   17-α-hydroxy-17-β-(3-furyl)-14-β, 15-β-epoxy-5-β-androstan-3-one;   3-guanidinoimino-17-β-(3-furyl)-14-β, 15-β-epoxy-5-β-androstan-17-α-ol;   14-β, 15-β-epoxy-17-β-(4-pyridazinyl)-5-β-androstane-3-β, 17-α-diol;   and the 3 alpha derivatives of the above identified 3-β derivatives and also the corresponding 3 alpha and 3-β thioderivatives where Y═S.   
     
     
         5 . Use of a compound of formula (I) of  claim 1 , for preparing a medicament for the prevention and/or treatment of proteinuria, glomerulosclerosis and renal failure. 
     
     
         6 . Use according to  claim 5 , in which the preferred compound is 17-β-(3-Furyl)-5-β-androstane-3-β, 14-β, 17-α-triol. 
     
     
         7 . Use according to  claim 5 , in which the compound is administered in a dose of from 0.05 mg to 20 mg per day. 
     
     
         8 . Use according to  claim 7 , in which the compound is administered in a dose of from 0.5 mg to 15 mg. 
     
     
         9 . Use according to  claim 8 , in which the compound is administered in a dose of from 5 mg to 10 mg. 
     
     
         10 . Use according to  claims 7 - 9  in which the compound is administered in a single dose schedule. 
     
     
         11 . Use according to  claims 7 - 9 , in which the compound is administered in a multiple dose schedule. 
     
     
         12 . Use according to  claim 5 , in which the medicament is for oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, transcutaneous, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration.